Interplay of tau and functional network connectivity in progressive supranuclear palsy: a [18F]PI-2620 PET/MRI study.

PURPOSE: Progressive supranuclear palsy (PSP) is primary 4-repeat tauopathy. Evidence spanning from imaging studies indicate aberrant connectivity in PSPs. Our goal was to assess functional connectivity network alterations in PSP patients and the potential link between regional tau-burden and network-level functional connectivity using the next-generation tau PET tracer [18F]PI-2620 and resting-state functional MRI (fMRI). MATERIAL AND METHODS: Twenty-four probable PSP patients (70.9 ± 6.9 years, 13 female), including 14 Richardson syndrome (RS) and 10 non-RS phenotypes, underwent [18F]PI-2620 PET/MRI imaging. Distribution volume ratios (DVRs) were estimated using non-invasive pharmacokinetic modeling. Resting-state fMRI was also acquired in these patients as well as in thirteen older non-AD MCI reference group (64 ± 9 years, 4 female). The functional network was constructed using 141 by 141 region-to-region functional connectivity metrics (RRC) and network-based statistic was carried out (connection threshold p < 0.001, cluster threshold pFDR < 0.05). RESULTS: In total, 9870 functional connections were analyzed. PSPs compared to aged non-AD MCI reference group expressed aberrant connectivity evidenced by the significant NBS network consisting of 89 ROIs and 118 connections among them (NBS mass 4226, pFDR < 0.05). Tau load in the right globus pallidus externus (GPe) and left dentate nucleus (DN) showed significant effects on functional network connectivity. The network linked with increased tau load in the right GPe was associated with hyperconnectivity of low-range intra-opercular connections (NBS mass 356, pFDR < 0.05), while the network linked with increased tau load in the left cerebellar DN was associated with cerebellar hyperconnectivity and cortico-cerebellar hypoconnectivity (NBS mass 517, pFDR < 0.05). CONCLUSIONS: PSP patients show altered functional connectivity. Network incorporating deep gray matter structures demonstrate hypoconnectivity, cerebellum hyperconnectivity, while cortico-cortical connections show variable changes. Tau load in the right GPe and left DN is associated with functional networks which strengthen low-scale intra-opercular and intra-cerebellar connections and weaken opercular-cerebellar connections. These findings support the concept of tau load-dependent functional network changes in PSP, by that providing evidence for downstream effects of neuropathology on brain functionality in this primary tauopathy.

DNA from resin-embedded organisms: Past, present and future.

Past claims have been made for fossil DNA recovery from various organisms (bacteria, plants, insects and mammals, including humans) dating back in time from thousands to several million years BP. However, many of these recoveries, especially those described from million-year-old amber (fossil resin), have faced criticism as being the result of modern environmental contamination and for lack of reproducibility. Using modern genomic techniques, DNA can be obtained with confidence from a variety of substrates (e.g. bones, teeth, gum, museum specimens and fossil insects) of different ages, albeit always less than one million years BP, and results can also be obtained from much older materials using palaeoproteomics. Nevertheless, new attempts to determine if ancient DNA (aDNA) is present in insects preserved in 40 000-year old sub-fossilised resin, the precursor of amber, have been unsuccessful or not well documented. Resin-embedded specimens are therefore regarded as unsuitable for genetic studies. However, we demonstrate here, for the first time, that although a labile molecule, DNA is still present in platypodine beetles (Coleoptera: Curculionidae) embedded in six-year-old and two-year-old resin pieces from Hymenaea verrucosa (Angiospermae: Fabaceae) collected in Madagascar. We describe an optimised method which meets all the requirements and precautions for aDNA experiments for our purpose: to explore the DNA preservation limits in resin. Our objective is far from starting an uncontrolled search for aDNA in amber as it was in the past, but to start resolving basic aspects from the DNA preservation in resin and search from the most modern samples to the ancient ones, step by step. We conclude that it is therefore possible to study genomics from resin-embedded organisms, although the time limits remain to be determined.

Fluoridation of a lizard bone embedded in Dominican amber suggests open-system behavior.

Vertebrate fossils embedded in amber represent a particularly valuable paleobiological record as amber is supposed to be a barrier to the environment, precluding significant alteration of the animals' body over geological time. The mode and processes of amber preservation are still under debate, and it is questionable to what extent original material may be preserved. Due to their high value, vertebrates in amber have never been examined with analytical methods, which means that the composition of bone tissue in amber is unknown. Here, we report our results of a study on a left forelimb from a fossil Anolis sp. indet. (Squamata) that was fully embedded in Miocene Dominican amber. Our results show a transformation of the bioapatite to fluorapatite associated with a severe alteration of the collagen phase and the formation of an unidentified carbonate. These findings argue for a poor survival potential of macromolecules in Dominican amber fossils.

Combined PET/MRI: Global Warming-Summary Report of the 6th International Workshop on PET/MRI, March 27-29, 2017, Tübingen, Germany.

The 6th annual meeting to address key issues in positron emission tomography (PET)/magnetic resonance imaging (MRI) was held again in Tübingen, Germany, from March 27 to 29, 2017. Over three days of invited plenary lectures, round table discussions and dialogue board deliberations, participants critically assessed the current state of PET/MRI, both clinically and as a research tool, and attempted to chart future directions. The meeting addressed the use of PET/MRI and workflows in oncology, neurosciences, infection, inflammation and chronic pain syndromes, as well as deeper discussions about how best to characterise the tumour microenvironment, optimise the complementary information available from PET and MRI, and how advanced data mining and bioinformatics, as well as information from liquid biomarkers (circulating tumour cells and nucleic acids) and pathology, can be integrated to give a more complete characterisation of disease phenotype. Some issues that have dominated previous meetings, such as the accuracy of MR-based attenuation correction (AC) of the PET scan, were finally put to rest as having been adequately addressed for the majority of clinical situations. Likewise, the ability to standardise PET systems for use in multicentre trials was confirmed, thus removing a perceived barrier to larger clinical imaging trials. The meeting openly questioned whether PET/MRI should, in all cases, be used as a whole-body imaging modality or whether in many circumstances it would best be employed to give an in-depth study of previously identified disease in a single organ or region. The meeting concluded that there is still much work to be done in the integration of data from different fields and in developing a common language for all stakeholders involved. In addition, the participants advocated joint training and education for individuals who engage in routine PET/MRI. It was agreed that PET/MRI can enhance our understanding of normal and disrupted biology, and we are in a position to describe the in vivo nature of disease processes, metabolism, evolution of cancer and the monitoring of response to pharmacological interventions and therapies. As such, PET/MRI is a key to advancing medicine and patient care.

Comparison of volumetric and functional parameters in simultaneous cardiac PET/MR: feasibility of volumetric assessment with residual activity from prior PET/CT.

OBJECTIVE: To compare cardiac left ventricular (LV) parameters in simultaneously acquired hybrid fluorine-18-fluorodeoxyglucose ([18F] FDG) positron emission tomography/magnetic resonance imaging (PET/MRI) in patients with residual tracer activity of upstream PET/CT. METHODS: Twenty-nine patients (23 men, age 58±17 years) underwent cardiac PET/MRI either directly after a non-cardiac PET/CT with homogenous cardiac [18F] FDG uptake (n=20) or for viability assessment (n=9). Gated cardiac [18F] FDG PET and cine MR sequences were acquired simultaneously and evaluated blinded to the cross-imaging results. Image quality (IQ), end-diastolic (LVEDV), end-systolic volume (LVESV), ejection fraction (LVEF) and myocardial mass (LVMM) were measured. Pearson correlation and intraclass correlation coefficient (ICC), regression and a Bland-Altman analysis were assessed. RESULTS: Except LVMM, volumetric and functional LV parameters demonstrated high correlations (LVESV: r=0.97, LVEDV: r=0.95, LVEF: r=0.91, LVMM: r=0.87, each p<0.05), but wide limits of agreement (LOA) for LVEDV (-25.3-82.5ml); LVESV (-33.1-72.7ml); LVEF (-18.9-14.8%) and LVMM (-78.2-43.2g). Intra- and interobserver reliability were very high (ICC≥0.95) for all parameters, except for MR-LVEF (ICC=0.87). PET-IQ (0-3) was high (mean: 2.2±0.9) with significant influence on LVMM calculations only. CONCLUSION: In simultaneously acquired cardiac PET/MRI data, LVEDV, LVESV and LVEF show good agreement. However, the agreement seems to be limited if cardiac PET/MRI follows PET/CT and only the residual activity is used. KEY POINTS: • [ 18 F] FDG PET-MRI is feasible with residual [ 18 F] FDG activity in patients with homogenous cardiac uptake. • Cardiac volumes and function assessed by PET/MRI show good agreement. • LVEDV and LVESV are underestimated; PET overestimates LVMM and LVEF. • Cardiac PET and MRI data correlate better when acquired simultaneously than sequentially. • PET and MRI should not assess LV parameters interchangeably.

[Amyloid positron-emission-tomography with [18 F]-florbetaben in the diagnostic workup of dementia patients]. / Amyloid-Positronenemissionstomographie mit [18 F]-Florbetaben in der Demenzdiagnostik.

BACKGROUND: To this day the definite diagnosis of Alzheimer's disease still relies on post-mortem histopathological detection of neurofibrillary tangles and beta-amyloid deposits. Amyloid positron emission tomography (PET) is a new diagnostic tool that enables the in vivo quantification of pathological beta-amyloid deposits. The aim of the current study was to evaluate to what extent 18F-florbetaben-PET (FBB-PET) influences the diagnosis of patients with dementia. MATERIAL AND METHODS: Imaging with FBB-PET was performed on 33 patients from our outpatient department for cognitive neurology. Beforehand all patients underwent a comprehensive clinical, neuropsychiatric and laboratory examination as well as imaging by means of magnetic resonance imaging (MRI) and fluorodeoxyglucose-PET. The working diagnoses before and after FBB-PET imaging were compared. RESULTS: 17 out of 33 patients were scored as FBB-PET positive. In four cases the initial diagnosis had to be changed to Alzheimer's disease (three cases) and cerebral amyloid angiopathy (one case) due to the positive FBB-PET scan. 16 patients showed a negative FBB-PET scan. In three patients the initial diagnosis of Alzheimer's disease could be ruled out due to the negative FBB-PET scan. Overall, in 7 out of 33 examined patients the initial diagnosis had to be changed because of the findings of the FBB-PET scan. In 24 patients the initial diagnosis was confirmed by the results of the FBB-PET scan. CONCLUSION: Amyloid-PET is currently no standard procedure in the diagnosis of dementia; however, it can be a helpful additional diagnostic tool when used according to the "Appropriate Use Criteria" and the S3 guidelines on dementia in cases of unclear clinical presentation, atypically early age of onset as well as in patients with persistent or progressive unexplained mild cognitive impairment. By facilitating early diagnosis amyloid-PET imaging allows patient selection for therapeutic drug trials.

Combined PET/MRI: from Status Quo to Status Go. Summary Report of the Fifth International Workshop on PET/MR Imaging; February 15-19, 2016; Tübingen, Germany.

This article provides a collaborative perspective of the discussions and conclusions from the fifth international workshop of combined positron emission tomorgraphy (PET)/magnetic resonance imaging (MRI) that was held in Tübingen, Germany, from February 15 to 19, 2016. Specifically, we summarise the second part of the workshop made up of invited presentations from active researchers in the field of PET/MRI and associated fields augmented by round table discussions and dialogue boards with specific topics. This year, this included practical advice as to possible approaches to moving PET/MRI into clinical routine, the use of PET/MRI in brain receptor imaging, in assessing cardiovascular diseases, cancer, infection, and inflammatory diseases. To address perceived challenges still remaining to innovatively integrate PET and MRI system technologies, a dedicated round table session brought together key representatives from industry and academia who were engaged with either the conceptualisation or early adoption of hybrid PET/MRI systems. Discussions during the workshop highlighted that emerging unique applications of PET/MRI such as the ability to provide multi-parametric quantitative and visual information which will enable not only overall disease detection but also disease characterisation would eventually be regarded as compelling arguments for the adoption of PET/MR. However, as indicated by previous workshops, evidence in favour of this observation is only growing slowly, mainly due to the ongoing inability to pool data cohorts from independent trials as well as different systems and sites. The participants emphasised that moving from status quo to status go entails the need to adopt standardised imaging procedures and the readiness to act together prospectively across multiple PET/MRI sites and vendors.

Impact of attenuation correction on clinical [(18)F]FDG brain PET in combined PET/MRI.

BACKGROUND: In PET/MRI, linear photon attenuation coefficients for attenuation correction (AC) cannot be directly derived, and cortical bone is, so far, usually not considered. This results in an underestimation of the average PET signal in PET/MRI. Recently introduced MR-AC methods predicting bone information from anatomic MRI or proton density-weighted zero-time imaging may solve this problem in the future. However, there is an ongoing debate if the current error is acceptable for clinical use and/or research. METHODS: We examined this feature for [(18)F] fluorodeoxyglucose (FDG) brain PET in 13 patients with clinical signs of dementia or movement disorders who subsequently underwent PET/CT and PET/MRI on the same day. Multiple MR-AC approaches including a CT-derived AC were applied. RESULTS: The resulting PET data was compared to the CT-derived standard regarding the quantification error and its clinical impact. On a quantitative level, -11.9 to +2 % deviations from the CT-AC standard were found. These deviations, however, did not translate into a systematic diagnostic error. This, as overall patterns of hypometabolism (which are decisive for clinical diagnostics), remained largely unchanged. CONCLUSIONS: Despite a quantitative error by the omission of bone in MR-AC, clinical quality of brain [(18)F]FDG is not relevantly affected. Thus, brain [(18)F]FDG PET can already, even now with suboptimal MR-AC, be utilized for clinical routine purposes, even though the MR-AC warrants improvement.

Simultaneous [18F]FDG-PET/MRI: Correlation of Apparent Diffusion Coefficient (ADC) and Standardized Uptake Value (SUV) in Primary and Recurrent Cervical Cancer.

OBJECTIVES: Previous non-simultaneous PET/MR studies have shown heterogeneous results about the correlation between standardized uptake values (SUVs) and apparent diffusion coefficients (ADCs). The aim of this study was to investigate correlations in patients with primary and recurrent tumors using a simultaneous PET/MRI system which could lead to a better understanding of tumor biology and might play a role in early response assessment. METHODS: We included 31 patients with histologically confirmed primary (n = 14) or recurrent cervical cancer (n = 17) who underwent simultaneous whole-body 18F-FDG-PET/MRI comprising DWI. Image analysis was performed by a radiologist and a nuclear physician who identified tumor margins and quantified ADC and SUV. Pearson correlations were calculated to investigate the association between ADC and SUV. RESULTS: 92 lesions were detected. We found a significant inverse correlation between SUVmax and ADCmin (r = -0.532, p = 0.05) in primary tumors as well as in primary metastases (r = -0.362, p = 0.05) and between SUVmean and ADCmin (r = -0.403, p = 0.03). In recurrent local tumors we found correlations for SUVmax and ADCmin (r = -0.747, p = 0.002) and SUVmean and ADCmin (r = -0.773, p = 0.001). Associations for recurrent metastases were not significant (p>0.05). CONCLUSIONS: Our study demonstrates the feasibility of fast and reliable measurement of SUV and ADC with simultaneous PET/MRI. In patients with cervical cancer we found significant inverse correlations for SUV and ADC which could play a major role for further tumor characterization and therapy decisions.

Combined PET/MRI: Multi-modality Multi-parametric Imaging Is Here: Summary Report of the 4th International Workshop on PET/MR Imaging; February 23-27, 2015, Tübingen, Germany.

This paper summarises key themes and discussions from the 4th international workshop dedicated to the advancement of the technical, scientific and clinical applications of combined positron emission tomography (PET)/magnetic resonance imaging (MRI) systems that was held in Tübingen, Germany, from February 23 to 27, 2015. Specifically, we summarise the three days of invited presentations from active researchers in this and associated fields augmented by round table discussions and dialogue boards with specific topics. These include the use of PET/MRI in cardiovascular disease, paediatrics, oncology, neurology and multi-parametric imaging, the latter of which was suggested as a key promoting factor for the wider adoption of integrated PET/MRI. Discussions throughout the workshop and a poll taken on the final day demonstrated that attendees felt more strongly that PET/MRI has further advanced in both technical versatility and acceptance by clinical and research-driven users from the status quo of last year. Still, with only minimal evidence of progress made in exploiting the true complementary nature of the PET and MRI-based information, PET/MRI is still yet to achieve its potential. In that regard, the conclusion of last year's meeting "the real work has just started" still holds true.

Combined PET/MR: The Real Work Has Just Started. Summary Report of the Third International Workshop on PET/MR Imaging; February 17-21, 2014, Tübingen, Germany.

This paper summarises the proceedings and discussions at the third annual workshop held in Tübingen, Germany, dedicated to the advancement of the technical, scientific and clinical applications of combined PET/MRI systems in humans. Two days of basic scientific and technical instructions with "hands-on" tutorials were followed by 3 days of invited presentations from active researchers in this and associated fields augmented by round-table discussions and dialogue boards with specific themes. These included the use of PET/MRI in paediatric oncology and in adult neurology, oncology and cardiology, the development of multi-parametric analyses, and efforts to standardise PET/MRI examinations to allow pooling of data for evaluating the technology. A poll taken on the final day demonstrated that over 50 % of those present felt that while PET/MRI technology underwent an inevitable slump after its much-anticipated initial launch, it was now entering a period of slow, progressive development, with new key applications emerging. In particular, researchers are focusing on exploiting the complementary nature of the physiological (PET) and biochemical (MRI/MRS) data within the morphological framework (MRI) that these devices can provide. Much of the discussion was summed up on the final day when one speaker commented on the state of PET/MRI: "the real work has just started".

Current status and future role of brain PET/MRI in clinical and research settings.

Hybrid PET/MRI systematically offers a complementary combination of two modalities that has often proven itself superior to the single modality approach in the diagnostic work-up of many neurological and psychiatric diseases. Emerging PET tracers, technical advances in multiparametric MRI and obvious workflow advantages may lead to a significant improvement in the diagnosis of dementia disorders, neurooncological diseases, epilepsy and neurovascular diseases using PET/MRI. Moreover, simultaneous PET/MRI is well suited to complex studies of brain function in which fast fluctuations of brain signals (e.g. related to task processing or in response to pharmacological interventions) need to be monitored on multiple levels. Initial simultaneous studies have already demonstrated that these complementary measures of brain function can provide new insights into the functional and structural organization of the brain.

Radioligand imaging of α4ß2* nicotinic acetylcholine receptors in Alzheimer's disease and Parkinson's disease.

The α4ß2* nicotinic acetylcholine receptors (α4ß2*-nAChR) are highly abundant in the human brain. As neuromodulators they play an important role in cognitive functions such as memory, learning and attention as well as mood and motor function. Post mortem studies suggest that abnormalities of α4ß2*-nAChRs are closely linked to histopathological hallmarks of Alzheimer's disease (AD), such as amyloid aggregates/oligomers and tangle pathology and of Parkinson's disease (PD) such as Lewy body pathology and the nigrostriatal dopaminergic deficit. In this review we summarize and discuss nicotinic receptor imaging findings of 2-[18F]FA-85380 PET, [11C]nicotine PET and 5-[123I]IA-85380 SPECT studies investigating α4ß2*-nAChR binding in vivo and their relationship to mental dysfunction in the brain of patients with AD and patients out of the spectrum of Lewy body disorders such as PD and Lewy body dementia (DLB). Furthermore, recent developments of novel α4ß2*-nAChR-specific PET radioligands, such as (-)[18F]Flubatine or [18F]AZAN are summarized. We conclude that α4ß2*-nAChR-specific PET might become a biomarker for early diagnostics and drug developments in patients with AD, DLB and PD, even at early or prodromal stages.

Topical therapies for osteoarthritis.

This review discusses the pharmacology, analgesic efficacy, safety and tolerability of topical NSAIDs, salicylates and capsaicin for the management of osteoarthritis (OA) pain. Topical therapies present a valuable therapeutic option for OA pain management, with substantial evidence supporting the efficacy and safety of topical NSAIDs, but less robust support for capsaicin and salicylates. We define topical therapies as those intended to act locally, in contrast to transdermal therapies intended to act systemically. Oral therapies for patients with mild to moderate OA pain include paracetamol (acetaminophen) and NSAIDs. Paracetamol has only weak efficacy at therapeutic doses and is hepatotoxic at doses >3.25 g/day. NSAIDs have demonstrated efficacy in patients with OA, but are associated with dose-, duration- and age-dependent risks of gastrointestinal, cardiovascular, renal, haematological and hepatic adverse events (AEs), as well as clinically meaningful drug interactions. To minimize AE risks, treatment guidelines for OA suggest minimizing NSAID exposure by prescribing the lowest effective dose for the shortest duration of time. Systemic NSAID exposure may also be limited by prescribing topical NSAIDs, particularly in patients with OA pain limited to a few superficial joints. Topical NSAIDs have been available in Europe for decades and were introduced to provide localized analgesia with minimal systemic NSAID exposure. Guidelines of the American Academy of Orthopaedic Surgeons, European League Against Rheumatism (EULAR), Osteoarthritis Research Society International, and National Institute for Health and Clinical Excellence (NICE) state that topical NSAIDs may be considered for patients with mild to moderate OA of the knee or hand, particularly in patients with few affected joints and/or a history of sensitivity to oral NSAIDs. In fact, the EULAR and NICE guidelines state that topical NSAIDs should be considered before oral therapies. Clinical trials of topical NSAIDs, most notably formulations of diclofenac and ketoprofen, have shown efficacy significantly superior to placebo and similar to oral NSAIDs. Most topical NSAIDs (piroxicam being the exception) have shown improved safety and tolerability compared with oral NSAIDs. Topical salicylates and capsaicin are available in the US without a prescription, but neither has shown substantial efficacy in clinical trials, and both have potential to cause serious AEs. Accidental poisonings have been reported with salicylates, and concerns exist that capsaicin-induced nerve desensitization is not fully reversible and that its autonomic nerve effects may increase the risk of skin ulcers in diabetic patients.

Safety and efficacy of topical diclofenac sodium gel for knee osteoarthritis in elderly and younger patients: pooled data from three randomized, double-blind, parallel-group, placebo-controlled, multicentre trials.

BACKGROUND: NSAIDs used for the treatment of osteoarthritis (OA) have dose-related risks for gastrointestinal, cardiovascular and renal adverse events (AEs), particularly in elderly patients. Topical NSAIDs reduce systemic NSAID exposure and may mitigate these risks. OBJECTIVE: To evaluate the safety and efficacy of topical diclofenac sodium 1% gel (DSG) versus vehicle in patients aged 25-64 or ≥65 years who have been diagnosed with knee OA. STUDY DESIGN: Pooled data from three 12-week, randomized, double-blind, parallel-group, multicentre trials. SETTING: US primary care, internal medicine, orthopaedic and rheumatology practices. PATIENTS: Aged ≥25 years with mild to moderate (Kellgren-Lawrence grade 1-3) knee OA. INTERVENTION: After a 1-week analgesic washout, patients applied 4 g of DSG or vehicle four times daily to one knee. Rescue paracetamol (acetaminophen) up to 4 g/day was allowed. MAIN OUTCOME MEASURE: Key efficacy outcomes common to the three trials were Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain (0-20) and physical function (0-68) subscales, global rating of disease (GRD; 100-mm visual analogue scale [VAS]) and pain on movement (POM; 100-mm VAS). ANOVA was used to compare efficacy outcome differences (DSG vs vehicle) by age (25-64 or ≥65 years). A flare design was used that defined a subset of patients who experienced increased pain during the washout period (modified efficacy subpopulation [MES]). RESULTS: The MES included both patients aged 25-64 (n = 602) and ≥65 (n = 374) years. Patients in each age group applied >90% of scheduled doses. Among patients aged 25-64 years, the improvement from baseline to week 12 (least squares mean [standard error]) was greater for DSG versus vehicle for WOMAC pain (-5.8 [0.3] vs -4.7 [0.3], p = 0.007), WOMAC physical function (-17.9 [0.9] vs -14.2 [0.9], p = 0.002), GRD (-29.5 [1.6] vs -23.8 [1.6], p = 0.01) and POM (-37.3 [1.8] vs -29.0 [1.8], p < 0.001). Among patients aged ≥65 years, the improvements from baseline for most efficacy outcome scores were significantly greater with DSG versus vehicle: WOMAC pain (-5.3 [0.3] vs -4.1 [0.4], p = 0.02), WOMAC physical function (-15.5 [1.1] vs -11.0 [1.1], p = 0.004) and POM (-33.7 [2.2] vs -26.4 [2.2], p = 0.02). The efficacy of DSG did not differ significantly between patients aged 25-64 years and ≥65 years: WOMAC pain (p = 0.85), WOMAC physical function (p = 0.70), GRD (p = 0.86) and POM (p = 0.81). The incidence of any AE was greater with DSG than with vehicle among patients aged 25-64 years (56.6% vs 50.8%) and ≥65 years (55.8% vs 43.9%). Treatment-related application site dermatitis was more common with DSG compared with vehicle in both younger (4.0% vs 0.7%, respectively) and older (5.8% vs 0.4%, respectively) patients and was the main reason for the difference in treatment-related AEs between the DSG and vehicle groups. Gastrointestinal AEs were infrequent among patients treated with DSG and similar to incidence rates with vehicle in both age groups. CONCLUSIONS: DSG was effective and generally well tolerated in adults regardless of age. These data support the topical application of DSG for relief of OA knee pain in elderly and younger patients. Clinicaltrials.gov registration numbers NCT00171626, NCT00171678, NCT00426621.

Topical nonsteroidal anti-inflammatory drugs for osteoarthritis.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are mainstays of the treatment of osteoarthritis (OA) but have dose- and age-related risks of gastrointestinal, cardiovascular, and renal adverse events (AEs). As a result, US and international guidelines recommend caution when prescribing oral NSAIDs, particularly in older patients and those with significant comorbidities. For OA of the hands and knees, topical NSAIDs provide efficacy similar to oral NSAIDs, with far less systemic distribution. Treatment-related cardiovascular, renal, and other serious AEs with topical NSAIDs have not been reported. At present, only 2 topical NSAIDs are approved in the United States for the treatment of OA: diclofenac sodium 1% gel for hand or knee OA and diclofenac sodium 1.5% in 45.5% dimethylsulfoxide solution for knee OA. Clinical trial data for these products have demonstrated efficacy superior to placebo or similar to oral diclofenac with AE profiles similar to placebo, except for application site reactions. In large double-blind trials, gastrointestinal AEs were infrequent and did not include ulcers, perforations, or bleeding. The purpose of this brief review is to examine the data from controlled double-blind trials evaluating the use of topical NSAIDs in patients with OA. Articles included were identified via a search of PubMed covering the period from January 1, 2005 through March 31, 2010. Reference lists from OA treatment guidelines and meta-analyses were reviewed for additional citations of importance.

Correlation of pain relief with physical function in hand osteoarthritis: randomized controlled trial post hoc analysis.

INTRODUCTION: Nonsteroidal anti-inflammatory drugs are recommended for the relief of pain associated with hand osteoarthritis (OA) but do not alter the underlying structural changes that contribute to impaired physical function. The current analysis examined the relationship of pain relief with measures of function and global rating of disease in patients with hand OA. METHODS: This was a combined analysis of 2 prospective, randomized, double-blind, 8-week, multicenter, parallel-group studies comparing diclofenac sodium 1% gel with placebo gel (vehicle) in patients with radiographically confirmed mild to moderate hand OA. Patients (n = 783) aged > or = 40 years applied diclofenac sodium 1% gel (2 g) or vehicle to each hand 4 times daily for 8 weeks. Outcome measures included pain intensity assessed on a 100-mm Visual Analog Scale (VAS); the Australian/Canadian Osteoarthritis Hand Index (AUSCAN) subscales for pain, stiffness, and physical function (100-mm VAS); and a global rating of disease (100-mm VAS). Change in VAS pain intensity from baseline to week 8 was categorized (<0%, 0%-<15%, 15%-<30%, 30%-<50%, 50%-<70%, and > or = 70%) without regard to treatment and compared in each category with the mean change from baseline in each AUSCAN subindex and the global rating of disease. Pearson correlations between changes in outcome measures from baseline to week 8 were calculated. RESULTS: Changes in VAS pain intensity were accompanied by similar changes in AUSCAN scores and global rating of disease. Pearson correlations confirmed significant associations (P < 0.001) between change in VAS pain intensity and changes in AUSCAN pain (correlation coefficient [r] = 0.81), AUSCAN function (r = 0.75), AUSCAN stiffness (r = 0.66), and global rating of disease (r = 0.76). CONCLUSIONS: Pain relief correlated with improvements in physical function, stiffness, and global rating of disease in patients with hand OA, irrespective of treatment. This suggests that pain or anticipation of pain inhibits physical function and influences patient perception of disease severity in hand OA. These results also suggest that any intervention to relieve the pain of hand OA may improve function and patient perception of disease severity, despite the absence of a disease-modifying mechanism of action. TRIAL REGISTRATION: Clinicaltrials.gov NCT00171652, NCT00171665.

Randomized controlled trial of diclofenac sodium gel in knee osteoarthritis.

OBJECTIVES: Nonsteroidal anti-inflammatory drugs have dose-related adverse effects. Topical nonsteroidal anti-inflammatory drugs may offer local efficacy with low systemic drug levels. This study assessed the efficacy and safety of topical diclofenac sodium 1% gel (DSG) in mild to moderate symptomatic knee osteoarthritis. METHODS: In a randomized, double-blind, vehicle-controlled trial, 492 adults aged >or=35 years with symptomatic knee osteoarthritis of >or=6 months' duration were randomized to DSG 4 g (n = 254) or vehicle (n = 238) 4 times daily for 12 weeks. Primary efficacy outcomes at week 12 were the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain subscale, WOMAC physical function subscale, and global rating of disease. Secondary outcomes included these outcomes assessed after 1, 4, and 8 weeks, and pain on movement assessed using a 100-mm visual analog scale. All adverse events were recorded. RESULTS: At week 12, the DSG group had significant decreases versus the vehicle group in mean WOMAC pain (P = 0.01), mean WOMAC physical function (P = 0.001), and mean global rating of disease (P < 0.001). Efficacy outcomes significantly favored DSG versus vehicle beginning at week 1. Application site reactions occurred in 5.1% and 2.5% of patients in the DSG and vehicle groups, respectively. The incidence of gastrointestinal disorders was 5.9% with DSG and 5.0% with vehicle. CONCLUSIONS: Over a 3-month treatment period, topical treatment with DSG achieved statistically and clinically significant improvements of pain and measures of physical function in patients with knee osteoarthritis.

Profound midbrain atrophy in patients with Wilson's disease and neurological symptoms?

Wilson's disease (WD) is characterized by impaired hepatic copper secretion and subsequent copper accumulation in many organs predominantly liver and brain, secondary to loss of function mutations in the copper transport protein ATP7B. If the disease is recognized too late or treatment is not adequate, brain copper accumulation leads to progressive neurodegeneration with a variety of clinical symptoms. The nigrostriatal dopaminergic system seems rather vulnerable. Midbrain atrophy, however, has not been recognized as one of the prime features of patients with WD. Here we report quantification of midbrain diameter in 41 patients with WD. Data were correlated to the severity of neurological symptoms and the integrity of dopaminergic neurons measured via dopamine transporter binding. For control, we measured midbrain diameter in 18 patients with no evidence for brainstem dysfunction and 5 patients with progressive supranuclear palsy (PSP). Patients with WD had a reduced midbrain diameter (15.5 +/- 0.4 mm) compared to controls (18.5 +/- 0.2 mm). WD patients without neurological symptoms had midbrain diameter that were not different from controls (18.0 +/- 0.3 mm), while patients with neurological symptoms showed midbrain atrophy similar to patients with PSP (14.4 +/- 0.3 mm versus 14.1 +/- 0.3). There was a strong and significant correlation between midbrain atrophy and the severity of neurological symptoms (r= -0.68, p < 0.001) while midbrain atrophy and dopamine transporter binding correlated significantly but was less pronounced (r=0.46, p < 0.001). In summary, we were able to show, that midbrain diameter is an easy to perform quantification of neurodegeneration induced by brain copper accumulation and that other structures than substantia nigra dopaminergic neurons seem to contribute to midbrain atrophy in WD.

Possible impact of dopamine SPECT on decision-making for drug treatment in Parkinsonian syndrome.

Single-photon emission computed tomography (SPECT) markers allow measuring the integrity of the brain dopaminergic system in vivo. We used dopamine transporter (DAT) SPECT with [(123)I]FP-CIT and dopamine D(2)/D(3) receptor SPECT with [(123)I]IBZM to evaluate whether there is a reduction of DAT and/or D(2)/D(3) receptor SPECT in treated and untreated patients with Parkinsonian syndrome (PS). We found that almost a quarter of our patients treated with anti-Parkinsonian medication prior to SPECT imaging did not show evidence of a presynaptic dopaminergic deficit while 37% of untreated patients were diagnosed as having Parkinson's disease. 17% of treated patients had additional loss of D(2)/D(3) receptor binding capacity in concordance with the clinical follow-up diagnoses of multiple system atrophy, progressive nuclear palsy, and vascular Parkinsonism. Apart from 38% clinically uncertain cases, SPECT was in concordance with 75% of initial clinical diagnoses. 25% were reclassified as indicated by SPECT findings and confirmed by a 1.5-year clinical follow-up. We conclude that dopamine SPECT may support establishing or refuting the clinical diagnosis and, therefore, help to make the decision for or against dopaminomimetic treatment in cases with PS.